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Abstract

Background: Despite prompt treatment, sepsis remains one of the leading factors of mortality in critically ill patients in intensive care units. This raises the importance to identify novel independent prognostic biomarkers to predict disease outcome.

Methods and Results: We have applied our previously published proteomics method for cardiac extracellular proteins (Barallobre-Barreiro et al, Circulation 2012) to biomarker discovery in septic hearts. C57Bl6 mice were injected with LPS, their cardiac proteome was subfractionated and extracellular proteins were analysed by liquid chromatography tandem mass spectrometry. Among the most differentially expressed proteins was long pentraxin 3 (PTX3), an acute phase protein, secreted by various cells and tissues, that is known to be associated with increased mortality in septic patients. Interestingly, PTX3 accumulated in the cardiac extracellular matrix as an octamer due to disulphide-bond formation. An octameric and tetrameric moiety of PTX3 was also detectable in plasma. For the first time, plasma levels of PTX3 monomers, tetramers and octamers were quantified in septic patients. On admission to the intensive care unit, there was no difference in octameric, tetrameric and monomeric PTX3 between survivors and non-survivors. However, over a time course of 11 days, reduction of octameric PTX3 to its monomeric form was associated with a greater survival after 28 days of follow-up. For example, on day 2 post admission, octameric PTX3 was undetectable in survivors, but still constituted more than half of total PTX3 in non-survivors (P<0.001). Levels of tetramer PTX3 were similar in the two groups. Interestingly, monomeric PTX3 levels were inversely correlated to the cardiac damage markers NT-proBNP, hsTnT and hsTnI.

Conclusion: Sepsis is associated with significant mortality. In comparison to the conventional measurements of total PTX3, the assessment of the oxidation state of PTX3 could be a superior predictor of disease outcome and resolution of inflammation in septic patients.